3,14-substituted-8-oxamorphinans

ABSTRACT

N-Substituted-3-hydroxy-8-oxamorphinans have been found to possess potent narcotic agonist and/or antagonist activity. In particular, the compound l-N-cyclopropylmethyl-3-hydroxy-14 Beta -methyl-8-oxamorphinan has been found to possess potent narcotic antagonist and agonist activity. These compounds are prepared by total synthesis and are not derived from opium alkaloids.

States Patent [191 Monkovic et a1.

[ Dec. 10, 1974 3,14-SUBSTITUTED-8-OXAMORPHINANS Inventors: Ivo Monliovic, Candiac, Quebec;

Yvon Lambert, Brossard, Quebec, both of Canada Bristol-Myers Company, New York, N.Y.

Filed: July 18, 1973 Appl. No.: 380,515

Assignee:

U.S. Cl. 260/293.55, 260/240 K, 260/247.7 E, 260/293.54, 260/570.5 R, 260/570.5 C, 260/DIG. 13, 424/267 Int. Cl C07d 99/04 Field of Search 260/293.55, 240 K, 247.7 E, 260/D1G. 13

References Cited UNITED STATES PATENTS 11/1969 Cross 260/268 3,480,638 11/1969 Block et a1 260/294.3 3,632,591 1/1972 Albertson et a]. 260/293.54 3,639,407 2/1972 Clarke et a1. 260/293.54 3,700,734 10/1972 Robinson et a1... 260/29354 3,732,233 5/1973 Pars et a1. 260/293.55 3,764,606 10/1973 Akkerman et a1. 260/293.54

Primary Examiner-G. Thomas Todd Attorney, Agent, or Firm-Robert E. Havranek [5 7] ABSTRACT 30 Claims, N0 Drawings 1 3,14-SUBSTITUTED-8-OXAMORPHINANS BACKGROUND OF THE INVENTION in which R is H or methyl and R is methyl or phenethyl as being moderate to weak analgetics.

B. Everette May, James Murphy. and J. Harrison Ager, J. Org. Chem. 25, 1386 (1960) report compounds having the formula HO R2 in which R is methyl or phenethyl and R is H or methyl as being potent analgetics.

C. Everette May, Hiroshi Kugita and J. Harrison Ager, J. Org. Chem. 26, 1621 (1961) report compounds having the formula in which R is methyl or phenethyl, R is methyl or H, R is H, OH or methoxy as producing varying degrees of analgesia.

D. Everette May, Colin Chignell and J. Harrison Ager, J. Med. Chem. 8, 235 (1965) report compounds having the formula in which R is H or methyl and R is methyl as possessing analgetic activity.

E. Everette May and Hiroshi Kugita, J. Org. Chem. 26 1954 (1961) report the compound having the formula in which R is methyl or phenethyl, R is H or methyl and R is H or acetyl as having analgetic activity.

F. Everette May and Seiichi Sato, J. Org. Chem. 26, 4536 (1961) report compounds having the formula qN-orr, 15 L 20 in which R is H or methyl, R is methyl or ethyl, R is methyl or ethyl and R is H or acetyl as possessing analgetic activity.

G. N. B. Eddy and E. L. May published a review of 6,7-benzomorphans in Synthetic Analgetics, Pergamon Press (1966).

SUMMARY OF THE INVENTION Compounds having the formula Y? 3 i O 5 U wherein R is selected from the group comprising H, (lower)alkyl,

and (lower)alkenyl in which R is H or CH R is selected from the group comprising H, (lower)alkyl,

and R is H or (lower)alkyl; or a pharmaceutically acceptable acid addition salt thereof are analgetic agents, narcotic antagonists or intermediates in the preparation of such agents.

DISCLOSURE OF THE INVENTION wherein R is selected from the group comprising H, (lower)alkyl,

we e

l Re

Iku

and (lower)alkenyl in which R is H or CH R is selected from the group comprising H, (lower)alkyl,

and cinnamoyl, and R is H or (lower)alkyl; or a pharmaceutically acceptable acid addition salt thereof.

Drug abuse by thrill-seeking youth or by people looking for an escape from the realities of every day life has become more and more common place in our present society. One class of widely abused drugs are the narcotic analgetics such as codeine, morphine, meperidine, etc. It is because of the high addictive potential of these segments that much time and money are being expended by the pharmaceutical industry and by gov ernments to try and discover and develop new nonaddicting analgetics and/or narcotic antagonists.

It was therefore an object of the present invention to develop low abuse analgetics and a synthesis that would not be dependent upon opium alkaloids as starting materials and yet would be commercially feasible.

The objectives of the present invention have been achieved by the provision of the compounds of formula L and by their total synthesis from the readily available starting material 7-methoxy-3,4-dihydro-2[1H]- naphthalenone.

The compounds of the instant invention have the basic oxamorphinan nucleus which is numbered and represented by the following plane formula Although there are three asymetric carbons (asterisks) in the oxamorphinan molecule, only two diastereoisomeric (racemic) forms are possible, because the iminoethano system, attached to position 13 and 9, is geometrically constrained to a cis( 1,3-diaxial)-fusion. These racemates can therefore differ only in the configuration of carbon 14. The only variable will be the cis and trans relationship of the 14 carbon substituent to the i m in oethfifwiri wheri irfthe "'earhpflfias of the present invention the l4-substituent(alkyl) is trans to the iminoethano system, we have the 14aalkyloxaisomorphinans. When the l4-alkyl is cis to the iminoethano system, we have the 143- alkyloxamorphinans.

The use of a graphic representation of a oxamorphinan is meant to include the d1 racemic mixture and the resolved d and l isomers thereof.

The compounds of the present invention, the 14a and 14B-alkyloxamorphinans, can exist as two optical isomers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphically illustrated as: 14B-alkyloxamorphinan:

The present invention embodies all of the isomers including the optical isomers in their resolved form.

The compounds of the invention are prepared from benzomorphinans having the basic nucleus which is numbered and represented by the following plane formula III CHaO- CHaO- VIIa For the purpose of this disclosure, the term (lower) is applied to a hydrocarbon radical consisting of l to 6 carbon atoms, e.g., methyl, ethoxy, vinyl, ethinyl, etc. The term (lower)alkanoyl is an alkanoyl radical of 2 to 6 carbon atoms, e.g., acetyl, propionyl, isobutyryl, etc. The term pharmaceutically acceptable acid addition salt is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts are commonly used to produce nontoxic salts of medicinal agents containing amine functions. Illustrative examples would be those salts formed by mixing the compounds of formula L with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric, tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic, lauryl sulfuric, naphthalinesulfonic, linoleic or linolenic acid, fumaric and the like.

e compoun s of the instant invention are prepared by a total synthesis comprising multiple steps. Surprisingly, the synthesis is efficient and appears commercially feasible. The process is outlined in the following charts.

CHART I Example HBr /CH3 /CH3 CH; IV CH3 Example CH3 CH3 69/ L CH3 Example CH3 O B ,6 CHaO- -O B .9

vm V

VIIIa.

A preferred embodiment of the present invention is the compounds having the formula R20 a xxxx 10 wherein R is selected from the group comprising L wherein R is selected from the group comprising -CHCECH, H, cm cn=om, crr, c11=c CH: 15 CH3 -CH -CECH, H, CH;CH=CH1, cH, CH=C Cm 3353i? lsl isl tl tlw in l and (lower)alkenyl in which R is H or CH R is selected from the group comprising H, (lower)alkyl, and (lower)alkenyl in which R is H or CH R is selected from the group comprising H, (lower)alkyl,

0 o N o N L i i gf and cinnamoyl, and R is H or (lower)alkyl; or a pharand cinnamoyl, and R is H or (lower)alkyl; or a pharmaceutically acceptable acid addition salt thereof. maceutically acceptable acid addition salt thereof. A more preferred embodiment is the compounds of Another preferred embodiment is the compounds the formula XXXX wherein R is CH -CH=CH H having the fomiula (lower)alkyl CH C I CH,

I I m m in which R is H or CH R is H,

o i i \N O, (lower) alkanoyl, & \N, and R 1S H, CH or C H or a pharmaceutically aca ceptable acid addition salt thereof.

0 0 Another more preferred embodiment is the com- P; pounds of formula XXXX wherein R is N and (lower)alkenyl in which R is H or CH R is selected from the group comprising H, (lowcr)alkyl,

I OH:

or CH -CH=CH R is H, CH or 0 N p N i CHa-' 8 W and R is methyl; or a pharmaceutically acceptable acid and cinnamoyl, and R is H or (lower)alkyl; or a pharaddition salt thereof. maceutically acceptable acid addition salt thereof.

Another preferred embodiment is the compounds A more preferred embodiment is the compounds of having the formula the formula XXXXl wherein R is CH -CH=CH --CH C CH,

4N-R cin -om-err=c -crn R, or 43mg R20 oin in which R is H or CH R is H, CH o. u KZQEP l I u n O 0 wherein R 18 selected from the group comprising CH4 1L or L CH3 a To 7 CH2 CECH, =C and R is H, CH or C H or a pharmaceutically ac- CH: 45 ceptable acid addition salt thereof o y Another more preferred embodiment is the compounds of formula XXXXI wherein R is addition salt thereof.

Most preferred embodiments are: 1 CH 1. The compound of formula XXXX wherein R is R", CH2L &

ll fl' 1 R is H, and R is methyl; or the hydrochloride salt -s o thereof.

and R is methyl; or a pharmaceutically acceptable acid OH1 -crn =crr, 6O

13 2. The compound of formula XXXX wherein R is 5 R is H, and R is methyl; or the hydrochloride salt thereof.

3. The compound of formula XXXX wherein R is -CH CH=CH R is H, and R is methyl; or the hydrochloride salt thereof.

4. The compound of formula XXXX wherein R is H, R is H or methyl; and R is H or methyl; or an acid addition salt thereof.

5. The compound of formula XXXXI where R is R is H and R is methyl; or the hydrochloride salt thereof.

6. The compound of formula XXXXI wherein R is 11. The levorotatory isomers of the compound XXXXI.

12. The dextrorotatory isomers of the compound XXXXI.

The processes for the preparation of the compounds of the instant invention are new and novel and also constitute preferred embodiments.

A preferred embodiment of the present invention is the process of preparing compounds having the formula W V 7 LI wherein R is selected from the group comprising 2 CH,

(lowcr)alkyl.

and (lower)alkenyl in which R is H or CH R is H or (lower)alkyl; which process comprises the consecutive steps of 30 A. treating the compound having the formula 5 0 XXXXIII 40 in which R is (lower)alkyl and R is as defined above, with an alkylating or acylating agent having the formula in which W is a radical selected from the group comprising 15 and C alkenyl in which R is H or CH Z is carbonyl I or CH and X is chloro, bromo, or iodo, in an inert organic solvent in the presence of an appropriate base to produce the compound having the formula in which R, Z, W, and R are as defined above; and when Z is carbonyl XXXXV in which R, W and R are as defined above; and

C. cleaving the ether function of compound XXXXIV or XXXXV by treatment with an agent selected from the group comprising NaS-C H hydrobromic acid, boron tribromide or pyridine hydrochloride.

For the purpose of this disclosure the term inert organic solvent means an organic solvent that does not participate in the reaction to the extent that it emerges unchanged from the reaction. Such solvents are methylene chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene, ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide, and the like when an acid halide is employed. When an alkylation reaction is being performed, the inert solvent used may also include (lower- )alkanols such as methanol, ethanol n-propanol, isopropanol and the like. The term organic tertiary amine means a tertiary amine commonly employed as a proton acceptor in acylation reactions. Such amines are tri(lower)alkylamines, e.g., trimethylamine, triethylamine, and the like, pyridine, dimethylaniline, N- methylpiperidine, and the like.

A preferred embodiment of the present invention is the process of preparing compounds having the formula 10 wherein R is selected from the group comprising and C alkenyl in which R is H or CH R is H or (lower)alkyl; which process comprises the consecutive steps of A. treating the compound having the formula z s l M V I XXXXIIIa.

in which R" is (lower)alkyl and R is as defined above, with an alkylating or acylating agent having the formula H1 (lower) alkyl R CH:

and C alkenyl in which R is H or CH Z is carbonyl or CH and X is chloro, bromo or iodo, in an inert organic solvent in the presence of an appropriate base to produce the compound having the formula XXXXIVa in which R3, Z, W and R are as defined above; and when Z is carbonyl preparing compounds having the formula XXXXb wherein R is selected from the group comprising E CH, CH2 CH=CH2,

and C alkenyl and R is H or (lower) alkyl; which process comprises the consecutive steps of A treating the compound having the formula XXXXIIIa in which R is (lower)alkyl and R is as defined above; with an alkylating agent having the formula in which R is as above and X is chloro, bromo or iodo, in an inert organic solvent in the presence of an appropriate base to produce the compound having the formula XXXXlVb in which R, R and R are as defined above; and

B. cleaving the ether function of compound XXXXIVb by treatment with NaS-C H boron tribromide or pyridine hydrochloride.

More preferred embodiments are the process for the preparation of compounds of formula XXXXb wherein;

1. In step A R is methyl, R is H or methyl; the inert organic solvent is methylene chloride, dichloroethane or a (lower)alkanol, the base is pyridine, triethylamine or an alkali metal hydroxide or carbonate and the reaction is conducted at about 15 C. to about reflux temperature.

2. In step A R is methyl, R is methyl; the organic solvent is methanol, ethanol, n-propanol or isopropano], the base is triethylamine or sodium or potassium carbonate and the reaction is conducted at about reflux temperature for about 5 to about 20 hours.

A preferred embodiment of the present invention is the process for the preparation of the compound having the formula which process comprises the consecutive steps of A. hydrating the compound having the formula XII OII

in which R and R are (lwer)alkyl and R is H or (lower)alkyl, by treatment with borane, alkali metal base (sodium hydroxide) and hydrogen peroxide to produce the compound having the formula CI'IEO}I VIII in which R, R and R are as above;

B. sulfonating compound Vlll with a large excess of a (lower)alkyl or arylsulfonyl halide to produce the compound having the formula CHzOSOrZ in which R R and R are as above and Z is (lower)alkyl or aryl;

C. cyclizing compound IX by treatment with an excess of sodium hydride to produce the compound having the formula in which R, R and R are as above;

D. treating compound X with cyanogen bromide to produce the compound having the formula XII in which R is methyl and R is H or (lower)alkyl, which process comprises the consecutive steps of A. hydrating the compound having the formula in which R and R are methyl and R is H or (lower) alkyl, by treatment with an excess of borane, slight excess of an alkali metal hydroxide (sodium hydroxide) and hydrogen peroxide to produce the compound having the formula l CH2O ll in which R, R and R are as above;

B. sulfonating compound Vlllp with a large excess of a (lower)alkyl or arylsulfonyl halide to produce the compound having the formula VIIIp CHzOS 02 Z IXp in which R R and R are as above and Z is (lower)alkyl or aryl;

C. cyclizing compound IXp by treatment with an excess of sodium hydride in an inert organic solvent (benzene, toluene, xylene or the like) to produce the compound having the formula in which R, R and R are as above;

D. treating compound X with hydrogen bromide to produce the compound having the formula XIp tion is the process for the preparation of the compound having the formula XIIZ in which R is methyl and R is H or (lower)alkyl, which process comprises the consecutive steps of A. hydrating the compound having the formula VIIZ W e H V vnrz in which R, R and R are as above; sulfonating compound Vlllz with a large excess of a (lower)alkyl or arylsulfonyl halide to produce the compound having the formula CIIEOSOQZ in which R", R and R are as above and Z is (lower)alkyl or aryl;

C. cyclizing compound lXz by treatment with an ex cess of sodium hydride in an inert organic solvent (benzene, toluene, xylene or the like), to produce the compound having the formula in which R, R and R are as above;

D. treating compound Xz with cyanogen bromide to produce the compound having the formula in which R, R and R are as above; and

E. treating compound Xlz with lithium aluminum hydride in an inert solvent to produce the compound having the formula XIIz.

All of the compounds of the preferred embodiments herein are novel and valuable for their properties as analgesic and/or narcotic antagonist agents, or as intermediates in the preparation of compounds having these biological activities.

In particular, the compounds having the formula XV are those which possess the most desirable properties; i.e., analgesic and/or narcotic antagonist properties. Some of these compounds also possess antitussive activity, a property generally inherent with analgetic activity in similar series.

It is well known in the narcotic analgesic prior art that it is possible for some compounds to possess both agonist and antagonist properties. An agonist is a compound that imitates a narcotic analgesic and possesses analgetic qualities. An antagonist is a compound that counteracts the analgetic and euphoric properties of a narcotic analgetic. It is possible for a compound to have both properties. A good example of such a compound is cyclazocine.

In vivo testing was conducted on the compounds desi gnated herein as XVc (racemic mixture), d-XVc (dextrorotatory isomer), l-XVc (levorotatory isomer) and dl-XVd (see examples for structures) to determine their agonist and/or antagonist properties. Table 1 represents the results of the experiments. The figures reported are the number of milligrams/kilogram of body weight of compound that produced an agonist or antagonist effect in 50% of the mice and rats so tested 50- TABLE I 50 (mg-lkg.)

Agonist Activity Antagonist Activity Phenylquinone Writhin Oxymorphone Oxymorphone Morphine Antagonism Mouse at Straub Tail Narcosis Rat Tail Fllck Test Compounds SC PO SC PO SC PO XVc tartratc 0.19 N.D. 0.03 4.0 0.61 N.D. 0.36 ND. 0.05 7.3 d-XVc tartrate 40 No. x15 ND. ND. ND. ND 20 ND. l-XVc tartratc 0.1 1 2.7 0.02 1.3 #12 14.6 0.014 1.25 0.021 6.3 XVc tartrate 0.07 N.D. =0.01 ND. 24 ND. 1.8 NB. 0.9 ND. Pcntazocinc 4.9 36 ND. ND. 12.0 187 10.0 90 12.2 82.2 Nalor hinc 0.77 15 ND. ND. 1.14 64 0.58 5.4 0.38 22.1 Lcval orphan 26.3 ND. ND. ND. 0.29 46 0.32 5.4 0.086 12.0

(poor dose response) Cyclazocine 0.047 4.0 ND. ND. 0.81 24 0.12 2.7 0.040 3.7 Naloxone 40 ND. ND. ND. 0.17 13.1 0 02 0.95 0.010 2.7

All the compounds were tested as the tartrates, but EXAMPLES the weights reported in mg./kg. are corrected and re- Example 1 ported 1n terms of the free base.

A 50 per cent reduction in number of phenylquinone induced writhings (Siegmund, E. A. et al., Proc. 11 Soc. B101. & Med. 95, 729; 1957). Antagonism of Straub Tail induced by oxymorphone 25 1 (2 mg./kg. sc.) in 50 per cent of mice. 5 0

Antagonism of righting reflex loss induced by oxymorphone (1.5 mg./l g. sc.) in 50 per cent of rats.

A 50 per cent reduction of analgesic effect induced by morphine (15 mg./kg. sc.) as measured by the rat tail flick procedure (Harris, L. S. and Pierson, A. K., J. Pharmacol. & Expt. Therap., 143, 141; 1964).

1ND. Not done.

It is apparent from the table that compound l-XVc exhibits potent agonist and antagonist activity upon parenteral and oral administration. All the compounds of formula XV of the present invention possess varying degrees of potency of the same activity. Similarly, as is inherent in most compounds of this type, the compounds possess some subsidiary anti-tussive activity.

The normal oral and parenteral dosage range of the compounds of formula XV in adult humans is in the range of about 0.1 to 50 mg. three to four times a day depending upon the route of administration and the particular compound administered.

It has been reported in the literature that the compound haloperidol, 4{4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone (Merck Index, 8th Edition, p. 515) has found some experimental use in the alleviation of narcotic addiction withdrawal symptoms. It is therefore an embodiment of the present invention to combine haloperidol with the narcotic antagonists of the instant invention, to produce a product not only preventing narcotic abuse, but at the same time providing supportive therapy in the absence of opiates.

Haloperidol is commonly administered orally in 0.5 to 5.0 mg. two or three times daily depending upon the severity of the illness. A dose of haloperidol in this range would be administered contemporaneously with an efiective dose of the narcotic antagonist to produce the desired result.

Other combinations would include the narcotic antagonists in combination with anti-anxiety agents such as chlorodiazepoxide and diazepam, or phenothiazines like chlorpromazine, promazine or methotrimeptrazine.

3,4-Dihydro-7-methoxyl -ally1-2( 1H )naphthalenone (11a).

To a stirred solution of 50 g. (0.284 mole) of la (3,4- dihydro-7-methoxy-2( 11-1)naphthalenone) dissolved in 200 ml. of dry benzene was added during 5-10 minutes and under nitrogen, 40.5 g. (0.5 mole) of pyrrolidine dissolved in 50 ml. of benzene. The mixture was refluxed for 1 hour and 5 ml. of water was collected in a Dean-Stark apparatus. The mixture was cooled and added slowly to 60.5 g. (0.5 mole) of allyl bromide dissolved in 300 ml. of benzene. The resulting mixture was refluxed for 3 hours. Then 200 ml. of water was added to the reaction and refluxing was resumed. After 30 minutes the mixture was cooled, the benzene layer was separated, washed with water, followed by water saturated with sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was distilled to give 52.20 g. yield) of Ila; b.p. 1061l2/O.- 01-005 mm. The infrared (1R) and Nuclear Magnetic Resonance (NMR) spectra were consistent with the structure.

Anal. calcd. for C H O C, 77.74; H,

3 ,4-Dihydro-7-methoxyl -allyl- 1 -(2-dimethy1aminoethyl )-2 l H )naphthalenone hydrobromide (111a A mixture of 400 ml. dry benzene, 22 g. (0.25 mole) of tert.-amyl alcohol and 10.62 g (0.25 mole) of sodium hydride was refluxed under N for 30 minutes or until all the hydride was consumed. Then 47.2 g. (0.22 mole) of Ila in 100 ml. of benzene was added slowly while distilling off the excess of amyl alcohol. Another 100 ml. of benzene was added and distilled ofi. Then 28 g. (0.3 mole) of 2-chloro-N,N dimcthylaminoethanc in 100 ml. of benzene was added dropwise. The reaction mixture was refluxed for 20 hours, washed twice with water, and diluted with ether and extracted with 1N HCl. The acidic extract was warmed to 60 C. for 1 hour, cooled and extracted with ether to recover g. of Ila. The acidic extract was then cooled, basified with NH OH and extracted with ether. It was dried over potassium carbonate, treated with charcoal and after filtration, with dry l-lBr. There was obtained 33.87 g. (61.5%) of HBr salt of llla. After recrystallization from methanol/ether it melted at l39-l40. The IR and NMR were consistent with the structure.

Anal. calcd. for C, H NO .HBr: C, 58.69;

Found: C, 58.63; H, 7.16; N, 3.59

Example 3 3-Bromo-3,4-dihydro-7-methoxyl allyll 2- dimethylaminoethy1-2( 1H)naphtha1enone hydrobromide (lVa).

To a stirred solution of 15 g. (41 mmole) of llla in 100 ml. of methylene chloride and 300 ml. tetrahydrofuran (THF) in the dark, a solution of 20.58 g. (41.5 mmole) pyrrolidone hydrotribromide in 300 ml. of THF was added over a 4 hour period. After the addition, the reaction mixture was left overnight at room temperature. The solvents were evaporated to dryness and the solid residue recrystallized from 700 m1. of isopropanol to give 12.7 g. (68.5%) of Na; m.p. 149150 C. The IR and NMR were consistent with the structure.

Anal. calcd for C H NO- BnHBr: C, 48.34;

Found: C, 48.64; H, 5.70; N, 3.14

Example 2'-Methoxy-2-methyl-5-allyl-9-oxo-6,7-benzomorphan methobromide (Va).

The l-[Br salt lVa 12.6 g., 0.028 mole) was dissolved in ice cold water, placed in a separatory funnel and covered with ether. Enough concentrated ammonium hydroxide was added to alkalinize the mixture and the free base of IV was extracted and separated are rapidly as possible. The ether was evaporated, and the residue was dissolved in acetone and left overnight. There was obtained 6.55 g. (65.5% yield) of solid Va. After recrystallization from isopropanol, it melted at l-177 C. The IR and NMR were consistent with the structure.

Anal. calcd for C H NO .CH BR.1/2H O: C, 57.60; H, 6.71; N, 3.73. Found: C, 57.44; H, 6.78; N, 3.58.

Example 5 ea /CH3 QNCH3 H CH 0- a on 2'-Methoxy-2-methy1-5-allyl-9,B-hydroxy-6,7- benzomorphan methobromide (Vla).

To a stirred suspension of Va [5.9 g., 0.0161 mole] in 50 ml. of anhydrous ethanol, was added 0.350 g. (.009 mole) of NaBl-l One hour after the addition, 0.8000 g. of 48% HBr diluted with 10 ml. of water was added in small portions, and the reaction mixture was evaporated to dryness. The residue was taken up into methylene chloride, the inorganic material was filtered off and the solution was dried over sodium sulfate and evaporated to dryness. The solid residue was dissolved in a minimum of isopropanol and enough ether was added to crystallize Vla. There was obtained 4.2 g. of Vla (72.3% yield); m.p. 193 C. The 1R and NMR spectra were consistent with the structure.

C, 58.69; H, 7.11; N, 3.80

Found: C, 58.89; H, 7.26; N, 3.71

Example 6 2-Methoxy-2-methyl-5-allyl-9B-hydroxy-6,7- benzomorphan (Vlla).

To 50 ml. of boiling l-octanol was added 4.87 g. (13.2 mmole) of Vla and the mixture was refluxed for 15 minutes. After cooling, the solution was diluted with ether and extracted with 2N HCl followed by two portions of 20 ml. of H 0. The aqueous extracts were washed with petroleum ether (essentially n-hexane) to eliminate the traces of octanol, basified with ammonium hydroxide and extracted with ether, dried over sodium carbonate and evaporated. The oily residue crystallized upon addition of cyclohexane. Recrystallization from cyclohexane afforded 2.2 g. of Vlla in a yield of 61% mp. 9394 C. The IR and NMR spectra are consistent with the structure.

Anal. calcd for C H NO C, 74.69; H,

Found: C, 74.64; H, 8.49; N, 5.12.

Example 7 2--llydrosy-Z-methyl-5-allyl-9[?hydrox .'-6,7- benzomorphan (Villa A solution of 1 g. of Vlla (0.037 mole) in 20 ml. of dry methylene chloride was added slowly to a cooled (l C.) solution of 0.927 g. (.037 mole of BBr in 20 ml. of methylene chloride. Upon completion of the addition, the ice bath was removed and the reaction mixture was left at room temperature overnight. The content of the flask was poured on crushed ice and concentrated ammonium hydroxide, followed by extraction with chloroform. After drying over sodium sulfate, there was obtained 0.46 g. of Vllla as a solid; yield: 48%. 1t was recrystallized from toluene-petroleum ether; m.p. 6064 C. The IR and NMR spectra are consistent with the structure.

Anal. calcd. for C H NO z C. 74.09; H, 8.16; N,

5.40. Found: C, 74.73; H, 8.25; N, 5.30.

Example 8 2-Methoxy-2,9 x-dimethyl-5-allyl-9B-hydroxy-6,7- benzomorphan methiodide (Vlb).

To 5 g. 12.6 mmole) of Va was added rapidly a solution of Grignard reagent prepared from 11.35 g. (79 mmole) methyliodide and 2.07 g. (85.0 mole) magnesium in 50 ml. of ether. After the addition, the reaction was stirred at room temperature until all the solid had dissolved (approximately 2 hours), then water (5 ml.) was added to the solution while cooling, followed by ml. of 5N HCl and 5 g. of potassium iodide dissolved in 10 ml. of water. After stirring for 2 additional hours, the solid was filtered off. The product was recrystallized from water to give 4.3 g. (78% yield) of Vlb; m.p. 184-185 C. The IR and NMR were consistent with the structure.

Anal. calcd for C H NO 'CH l1/2H O: C, 52.06;

H, 6.66; N, 3.19. Found: C, 52.31; H, 6.56; N, 3.19.

Example 9 N cm /CPIa cmoon 2'-Methoxy-2,9a-dimethyl-5-ally1-9B-hydroxy-6,7- benzomorphan (Vllb).

To ml. of boiling l-octanol was added 9.00 g. of Vlb (0.021 mole) and the mixture refluxed for 15 minutes. After workup, as described in example 6, there was obtained 4.62 g. of Vllb as an oil which crystallized upon standing; m.p. 57 C. (Yield 75.5%). An oxalate salt was prepared and recrystallized from a mixture of methanol and ethyl ether; mp. C. (change l65l75). The IR and NMR spectra were consistent with the structure.

Anal. calcd. for C,,.H NO -C. H O, 1,311,011. k.

62.49; H, 7.54; N, 3.55. Found: C, 62.55; H, 7.19; N, 3.81

Example 10 2-Hydroxy-2,9a-dimethyl-5-allyl-9B-hydroxy-6,7- benzomorphan (Vlllb).

To a stirred and ice-salt cooled solution of 0.450 g. (1.7 mmole) BBr in 10 ml. of methylene chloride was added slowly 0.500 g. (1.7 mmole) of Vlla dissolved in 10 ml. of dry methylene chloride. After working up the reaction mixture as in example 7, there was obtained 0.47 g. of crude Vlllb. The crude material was dissolved in acetone and precipitated by oxalic acid. There was obtained 0.300 g. of the oxalate salt of Vlllb (47.5% yield). [t was recrystallized from acetone, m.p. (dec.). The IR and NMR spectra were consistent with the structure.

Found: C, 63.00; H, 7.01; N, 4.04

5 -Ally1-2 '-methoxy-2 ,9-dimethyl-9 a-hydroxy-6,7- benzomorphan Vllb and Vllc).

A solution of methyllithium in ether (71 m1 of a 5% solution, 115 mmol) was transferred with a syringe to XVla in 250 ml of dry petroleum ether (30-65). The

reaction mixture was then stirred at 20 25 for 19 hours. A solution of methyllithium in ether ml of a 5% solution, 24 mmol) was added and the mixture stirred for 1.5 hours to complete the reaction. Water was slowly added to destroy the excess of methyllithium and the organic phase was washed with water.

The water phase was extracted with ether, dried over sodium sulfate, and evaporated to dryness leaving 14.51 g (93%) of oil which was a mixture of Vllb (40%) and Vllc (60%) (estimated by NMR). The NMR spectrum showed two distinct signals for CI-I:(IJJOH at 8 1.0(11) and 6= l.58(lll) based on TMS (tetramethylsilane). After treatment with charcoal, the free base (13.05 g) was dissolved in 90 ml of 95% ethanol and added to a boiling solution of l 1.96 g of picric acid in 150 ml of 95% ethanol.

The solution was kept at 5 for 60 hoursand 21.88 g of a yellow solid which was a mixture of Vllb and Vllc (:80) was filtered. Two recrystallizations from dioxane and 95% ethanol afforded 15.3 g (58%) of the a-isomer Vllc m.p. 209 12.

Treatment of the free base with oxalic acid in methanol and ether gave a solid which after recrystallization afforded an analytical sample, m.p. 208-209 (VIlc).

Anal. calcd. fOI C gHNO2.C2H2O C 63.78; H 7.21; N 3.71.

Found: C 63.78; H 7.41; N 3.92

The mother liquor was concentrated and 6.16 g (24%) of the B-isomer Vllb crystallized out. Recrystallization from acetone ether gave a sample melting at l758. The free base was found to be identical with a sample obtained from example 9. The IR and NMR spectra were consistent with the structures.

Example 12 onloworn 9a-Hydroxy-2'-methoxy-2,9B-dimethyl-5-(propan-3- ol)-6,7-benzomorphan (Vlllc).

To a cooled (10, ice bath) solution of 0.69 g (2.4 mmol) Vllc in 24 ml of tetrahydrofuran was added 9.6 ml (9.6 mmol) of a 1M solution of borane in tetrahydrofuran. After 4 hours, 10 ml of a 1N solution of sodium hydroxide was added (dropwise for the first 0.5 ml) and 1.26 g 10.0 mmol) of a solution of hydrogen peroxide. After stirring for 1 hour at 2025 the solution was acidified with 20 ml of 1N hydrochloric acid, kept at 2025 for 0.5 hour and refluxed for 1 hour. The solvent was then evaporated in vacuo, the residue dissolved in dilute ammonium hydroxide and extracted with methylene chloride (4 X ml). The extracts were washed with water, dried (Na SO,) and evaporated to dryness leaving 0.77 g of an oil which was crystallized from benzene yielding 0.61 g (83%). A sample obtained from tetrahydrofuran-petroleum ether melted at l524 (Vlllc).

Anal. CalCd. for c d-1 N0 2 C, H,

Found: C, 71.17; H, 9.04; N, 4.44 The IR and NMR spectra were consistent with the structure.

Example 1 3 CHJO @0113 on l .9. T

9a-Hydroxy-2'-methoxy-2,9[3-dimethyl-5-(propane-3- mesylate)-6,7-benzomorphan (lXc).

To a solution of 0.61 g (2.0 mmol) Vlllc 20 ml of dry tetrahydrofuran and 2 ml of pyridine was added 1.14 g 10 mmol) of mesyl chloride. After stirring for 3 hours at 20, the solution was concentrated in vacuo, the oily residue dissolved in 250 ml of dilute hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried (Na SO and evaporated in vacuo leaving 0.85 g of light yellow oil. The hydrochloric acid salt was crystallized from methanolether yielding 0.61 g (79%) of lXc. Recrystallization from methanol-ether afforded an analytical sample, m.p. l435.

Anal. calcd. for C H N O S: C, 49.01; H,

Found: C, 49.03; H, 5.26; N, 9.16

Treatment of the free base with picric acid in acetone-ether gave the corresponding picrate, m.p. 1567.

Anal. calcd. for C H ClNO S: C, 54.34;

Found: C, 54.17; H, 7.23; N, 3.26 The IR and NMR spectra were consistent with the structure.

EXAMPLE 14 011,0 (gen.

3 -Methoxy- 14B-methyl-N-methyl-8-Oxamorphinan (Xc).

To a solution of 1.38 g (4.5 mmol) Vlllc in 50 ml of tetrahydrofuran and 5 ml of pyridine was added 1.76 ml (2.59 g, 22.5 mmol) of mesyl chloride. After stirring for 3 hours at 20, the solvent was evaporated in vacuo, the residual oil dissolved in dilute hydrochloric acid and extracted with ether. The water phase was then basifted with ammonium hydroxyde and extracted with methylene chloride. The methylene chloride extracts were washed with water, dried (Na SO and evaporated in vacuo leaving 1.89 g of brown oil. The crude oil thus obtained was dissolved in 30 ml of dry dimethylformamide placed in a flask under nitrogen, cooled to C (ice-salt bath) and treated with 0.43 g (9.0 mmol) of a 57% dispersion of sodium hydride in mineral oil washed twice with benzene. The cold bath was removed and the reaction mixture was stirred at 20 for 16 hours. The solution was cooled and the excess of sodium hydride was destroyed by careful addition of water. The solvent was evaporated in vacuo leaving a semi-solid residue which was dissolved in water, basified with ammonium hydroxide and extracted with methylene chloride. The organic extracts were washed with water, dried (Na SO and evaporated in vacuo leaving 1.28 g of brown oil. Dry column chromatography of the residue on an alumina column using chloroform as eluent gave 0.98 g (76%) of pure Xc. The hydrochloric acid salt was recrystallized from methanolether to give a sample melting at 242'44.

Anal. calcd. for C H ClNO C, 66.76; H, 8.09; N, 4.33 Found: C, 66.35; H, 7.93; N, 4.12 The IR and NMR were consistent with the structure.

N-Cyano-3-methoxy- 1 4B-methy1-8-oxamorphinan (Xlc).

A solution of 0.17 g (1.6 mmol) cyanogen bromide in 5 ml of chloroform was added dropwise to a solution of 0.38 g (1.3 mmol) Xc in 5ml of chloroform. After refluxing for 22 hours, the solvent was evaporated in vacuo and the residual oil crystallized from methanol giving 0.25 g (64%). The mother liquor was chromatographed on a column of silica gel. Elution with chloroform and 2.5% methanol-chloroform afforded 0.13 g (33%) of Xlc. An analytical sample m.p. 1578 was recrystallized from methanol.

Anal. calcd. for C H N O C, 72.45; H,

Found: C, 72.45; H, 7.50; N, 9.35.

The IR and NMR were consistent with the structure.

EXAMPLE 16 3-Methoxy-0b l4B-methyl-8-oxamorphinan (Xllc).

stirred solution of 0.30 g (8 mmol) lithium aluminum hydride in 30 ml of tetrahydrofuran under nitrogen. The reaction mixture was stirred at 0 for 15 min., gradually heated and refluxed for 3 hours. After cooling to 0, 0.3 ml of water, 0.22 ml of 20% sodium hydroxide and 1.05 ml of water were successively added. The reaction mixture was stirred at 20 for 20 min, the solid EXAMPLE 17 N-Cyclopropylcarbony1-3-methoxy- 1 4,8-methy1-8- oxamorphinan Xlllc.

A solution of 0.532 g (5.08 mmol) cyclopropyl carboxylic acid chloride in 25 ml of methylene chloride was added to a cooled (0, ice bath) solution of 1.39 g (5.08 mmol) Xllc in 50 ml of methylene chloride and 1.0 ml of triethylamine. After 1 hour at 0, the reaction mixture was diluted with 300 ml of methylene chloride, washed with 1N hydrochloric acid and water. The organic fraction was dried (Na SO and evaporated in vacuo leaving 1.97 g of oil which crystallized from ether-pet ether to yield 0.33 g (19%). The mother liquor was chromatographed on an alumina column. Elution with chloroform gave 0.93 g (53%) of amide Xlllc. The analytical sample, m.p. l413 was recrystallized from ether-petroleum ether.

Anal. calcd. for C ,H NO C, 73.87; H,

Found: C, 73.56; H, 8.03; N, 3.91.

The IR and NMR were consistent with the structure.

EXAMPLE 8 N-Cyclopropylmethyl-3-methoxy- 14B-methyl-8- oxymorphinan (XlVc).

To a cooled (ice-sa1t bath) and stirred solution of 152 mg (4.0 mmol) lithium aluminum hydride in 40 m1 of dry tetrahydrofuran was slowly added a solution of 0.69 g (2.0 mmol) Xlllc in 20 ml of dry tetrahydrofuran. The reaction mixture was then refluxed for 2 hours,

EXAMPLE 19 .ojjif N-Cyclopropylmethyl-3-hydroxyl4B-methyl-8- oxamorphinan XVc. Sodium thioethoxide method:

To a cooled ice bath suspension of 550 mg (13 mmol) of a 57% dispersion of sodium hydride in mineral oil previously washed twice with benzene, in 15 ml of dry dimethylformamide, under nitrogen, was added 1.05 ml, 887 mg 14 mmol) of ethanethiol. The suspension gradually became a clear solution. To the solution thus obtained was added 424 mg (1.3 mmol) of XlVc in 5 ml of dry dimethylformamide and the reaction mixture was gently refluxed for 3 hours. After cooling, the solution was poured on 250 ml of ice and water, the pH was adjusted to 8 with dilute hydrochloric acid and the aqueous phase was extracted with methylene chloride (4 X 100 ml). The extracts were dried (Na SO and evaporated in vacuo (0.4 mm Hg/40C) for 30 mins. leaving 458 mg of oil which was dry chromatographed on an alumina column. Elution with chloroform afforded 323 mg (79%) of phenol XVc. Crystallization of the hydrochloric acid salt of XVa from methanol-ether-dry HCl gas gave a sample melting at 268-70.

Anal. calcd. for C H ClNO C, 68.65; H,

Found: C, 68.81; H, 8.24; N, 3.79.

The IR and NMR spectra were consistent with the structure.

EXAMPLE 3-Hydroxyl 4B-methyl-N-methyl-8-oxymorphinan (XVllc.

To a cooled (0) solution of 0.50 g (1.67 mmol) Xc in 30 rnLof methylene chloride was added 6.68 mmol).

of a 1M solution of boron tribromide in methylene chloride and the solution was stirred at 0 for 2 hours. Then, 1 ml of 1N hydrochloric acid and 10 ml of water were added and the solution was stirred without cooling for 20 min. The reaction mixture was diluted with 200 ml of water and extracted with methylene chloride. The organic fraction was washed with water, dried (Na SO )and evaporated in vacuo leaving 0.48 g of amorphous material which was dry chromatographed on an alumina column. Elution with 5% methanol in chloroform gave 0.28 (59%) of the phenol XVllc. The hydrochloric acid salt of XVIIc was recrystallized from methanolether m.p. 25860.

Anal. calcd. for C H ,ClNO /2 CH OH:

C, 64.50; H, 8.04; N, 4.30

Found: C, 64.64; H, 7.97; N, 4.34 The 1R and NMR spectra were consistent with the structure.

EXAMPLE 21 crno- @011 5-Allyl-9B-hydroxy-2-methoxy-2-methyl-6,7- benzomorphan Vlld.

A solution of 0.27 g (1 mmol) XVla in 10 ml of ethanol was added to a solution of 45 mg of sodium borohydride in 10 ml of ethanol and the reaction mixture was refluxed for 1 hours. After cooling, the reaction mixture was neutralized with dilute HCl and the solvent was evaporated. The residue was treated with dilute ammonium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate and evaporated to dryness yielding 0.24 g (88%) of oil which crystallized from ether-petroleum ether; mp. 89.5 905.

The IR and NMR spectra were consistent with the structure.

EXAMPLE 22 CH: O

, ml (28.0 mmol) of a 1N sodium hydroxide solution was slowly added and then 0.91 g (8.0 mmol) of a 30% solution of hydrogen peroxide. After stirring at 20 for 1 hour the solvent was evaporated in vacuo and the residual aqueous phase extracted with ether. The organic extracts were dried (K CO and evaporated in vacuo leaving 2.72 g of residue which was dissolved in 25 ml of dioxane and 25 ml of glacial acetic acid. After refluxing for 30 mins. the solvent was evaporated under reduce pressure giving an oil which was diluted with water basified and extracted with ether. The combined extracts were dried (K CO and evaporated to dryness to yield 2.64 g of a yellow oil which was chromatographed on an alumina column. Elution with 1:1 petroleum ether-chloroform gave 0.30 g (14%) of the acetate of Vllld which was distilled at 160-5/ 0.01 mmHg.

Anal. calcd for C H NO C, 68.44; H,

Found: C, 68.28; H, 8.32; N, 3.92

Elution with 1:19 and 1:9 methanol-chloroform gave 1.71 g (74%) of diol Vllld which was crystallized from ether affording an analytical sample m.p. 98 100.

Anal. calcd. for C, H NO C, 70.07; H,

Found: C, 70.16; H, 8.79; N, 4.79. The IR and NMR spectra were consistent with the structures.

Example 23 3-Methoxy-N-methyl-S-oxaisomorphinan(Xd).

To a cooled ice bath solution of 1.08 g (3.71 mmol) Vllld in ml of methylene chloride and 0.12 ml of pyridine there was added 0.369 ml, [0.544 mg (5.19 mmol)] of mesyl chloride. After stirring for 24 hours at the solution was diluted with water, acidified with 1N hydrochloric acid and extracted with 100 ml of methylene chloride. The aqueous phase was basified with ammonium hydroxide and extracted with methyl ene chloride (3 X 100 ml). The combined basic extracts were dried (K CO and evaporated in vacuo leaving 1.48 g of an oil lXd.

The oil thus obtained was dissolved in 35 ml of dry dimethylformamide and placed in a flask under nitrogen. A suspension in 10 ml of dimethylformamide of 0.62 g of a 57% dispersion of sodium hydride in mineral oil washed twice with petroleum ether, was added. After stirring at 20 for 13 hours, the excess of hydride was destroyed with water and the solvent was evaporated in vacuo leaving 1.22 g of brown oil. The residue was chromatographed on an alumina column. Elution with chloroform gave 0.85 (84%) of Xd which was crystallized from ether-petroleum ether affording a sample melting at l045.

Anal. calcd. for C H NO C, 74.69; H,

Found: C, 74.74; H, 8.58; N, 5.11

Elution with 1:19 methanol-chloroform gave 0.21 g (16%) of starting material. The IR and NMR spectra were consistent with the structure.

Example 24 (N-CH:

3-Hydroxy-N-methyl-8-oxaisomorphinan XVlId.

To a cooled ice bath solution of 285 mg (1.05 mmol) Xd in dry methylene chloride was added 4.16 mm] (4.16 mmol) of a 1N solution of boron tribromide in methylene chloride. After stirring for 1 hour at 0 the mixture was diluted with water, basified with ammonium hydroxide and extracted with methylene chloride. The combined extracts were dried (K CO and evaporated in vacuo leaving 339 mg of solid material which was crystallized from acetone-methylene chloride giving 315 mg (94%) of XVlld. A sample m.p. 215-l9 was obtained from acetone.

Anal. calcd. for C H NO z C, 74.10; H,

Found: C, 74.21; H, 8.37; N, 5.25 The IR and NMR spectra were consistent with the structure.

EXAMPLE '25 2 '-Methoxy-2-methyl-5-allyl-9-oxo-6,7-benzomorphan XVIa.

A suspension of 2 g. (5.46 mmole) Va in 25 ml. octanol was heated under reflux and nitrogen atmosphere for 15 minutes. After cooling the mixture was poured into 40 ml. of 0.5N HCl and extracted twice with ml. of petroleum ether to remove octanol. The water layer was basified with aqueous ammonia and the free base extracted with benzene to yield, after drying and evaporation of solvent, 1.23 g. of an oil XVIa. The oil was stirred with a solution of 350 mg. oxalic acid in 5 ml. water for 1 hour, and it was left at 5 for 16 hours. Separated solid was filtered off to yield 980 mg. (47%) of XVIa oxalate, containing one mole of water of crystallization; m.p. 156162 C. The product recrystallized from water melted at 160l61 C with loss of water at 1 10 C.

Anal. calcd. for C, H NO 'C H O 'H O:

C, 60.15; H, 6.64; N, 3.69

Found: C, 60.52; H, 6.72; N, 3.70.

The IR and NMR spectra were consistent with the structure.

EXAMPLE 26 N-Cyano-3-methoxy-8-oxaisomorphinan (Xld Substitution in the procedure of Example 15 for compound Xc used therein of an equimolar quantity of Xd produces the compound Xld.

3-Methoxy-S-oxaisomorphinan (XIId).

Substitution in the procedure of Example 16 for compound Xlc used therein of an equimolar quantity of Xld produces the compound XlId.

EXAMPLE 28 N-Cyclopropylcarbonyl-3-methoxy-8- oxaisomorphinan (Xllld).

Substitution in the procedure of Example 17 for compound Xllc used therein of an equimolar quantity of Xlld produces the compound Xllld.

EXAMPLE 29 N-Cyclopropylmethyl-3-methoxy-8- oxaisomorphinan (XIVd).

Substitution in the procedure of Example 18 for compound Xlllc used therein of a equimolar quantity of Xllld produces compound XlVd.

Example 30 N-Cyclopropylmethyl-3-hydroxy-8-oxaisom0rphinan (XVd Substitution in the procedure of Example 19 for compound XlVc used therein of an equimolar quantity of XlVd produces compound XVd.

Example 31 N-Cyclobutylcarbonyl-3-methoxy-14B-methyl-8- oxamorphinan (Xllle).

A solution of 1.37 g (l 1 mmol) cyclobutylcarboxylic acid chloride in 20 ml of methylene chloride was added to a cold ice bath) solution of 2.86 g (10 mmol) Xllc in 30 ml of dry methylene chloride and 1.66 ml Example 32 N-Cyclobutylmethyl-3-methoxy- 14B-methyl-8- oxamorphinan (XlVe).

A solution of 3.43 g (9.7 mmol) XIIle in 50 ml of dry tetrahydrofuran was added dropwise (10 min) to a stirred solution of 0.74 g (19 mmol) lithium aluminum hydride in 50 ml of tetrahydrofuran. The reaction mixture was gradually heated and refluxed for 30 min. Then cooled (0, ice bath) and the excess of hydride was destroyed with 0.74 ml of water, 0.55 ml of 20% sodium hydroxide and 2.6 m1 of water. The solid was filtered off and the solvent evaporated in vacuo leaving 3.13 g of oil which crystallized from abs. ethanol to afford 0.93 g (28%) of XIVe. The mother liquor was chromatographed over aluminum oxide (dry column). Elution with benzene gave 1.03 g (31%) of XIVe. An analytical sample, m.p. 1057 was recrystallized from abs. ethanol. The IR and NMR spectra were consistent with the structure.

Anal. calcd. for C H N0 C, 77.38; H, 9.15; N, 4.10. Found: C, 77.84; H, 9.23; N, 4.09.

Example 33 N-Cyclobutylmethyl-3-hydroxyl 4B-methyl-8- oxamorphinan (XVe).

To a suspension of 1.33 g (32 mmol) of a 57% dispersion of sodium hydride in mineral oil washed (twice with benzene), in 25 ml of dimethyl formamide cooled in an ice bath, under nitrogen, was added dropwise 2.35 ml (32 mmol) of ethanethiol. The cold bath was removed and the reaction mixture was stirred at 20 25 until a clear solution was obtained (15 min). To the solution thus obtained was added a solution of 0.93 g (2.7 mmol) XlVe in 10 ml of dimethylformamide and the reaction mixture was gently refluxed (1536) for 2 hrs.

The cooled mixture was poured into dilute hydrochloric acid, basified with cone. ammonia and extracted with methylene chloride. The organic layer was extracted with N hydrochloric acid and the aqueous extracts basified with cone. ammonia, and extracted with methylene chloride. The organic phase was dried (Na S0 treated with charcoal and evaporated in vacuo affording 1.05 g of oil. The oil was chromatographed over g of silica gel (dry column). Elution with ml of chloroform followed by ether gave 0.70 g (78%) of XVe. The oxalate salt was prepared from methanolether. The IR and NMR spectra were consistent with the structure. Recrystallization of the oxalate from ethanol gave a sample melting at 132.

Anal. calcd. for C ,H NO .C H OH. l/2C H O C, 68.87; H, 8.67; N, 3.35.

Found: C, 68.76; H, 8.81; N, 3.31.

Example 34 N-Propargyl-3-methoxy- 14B-methyl-8-oxamorphinan (XlVf).

A mixture of 1.8 mmole [0.300 g.] of sodium bicarbonate and 0.225 g. (1.8 mmole) of propargyl bromide in 5 ml. of dry dimethylformamide (DMF) is stirred overnight at room temperature. The reaction mixture is then diluted with ether and filtered. The filtrate is extracted with 0.05N HCl, the layers separated and the acidic layer made alkaline with concentrated ammonium hydroxide before extraction with ether. After drying over potassium carbonate, compound XlVf is obtained upon evaporation of the ether in vacuo.

Example 35 N-Propargyl-3-hydroxy- 1 4B-methyl-8-oxamorphinan (XVf).

A solution of 1.35 mmole of XlVf in 10 ml. of methylene chloride is added slowly to a solution of 1.4 mmole (0.350 g.) of BBr in 10 ml. of methylene chloride maintained at 10 C. The resulting mixture is stirred overnight at room temperature. The contents of the flask are poured on crushed ice and concentrated ammonium hydroxide, followed by extraction with chloroform. After drying over sodium sulfate, the filtrate is evaporated in vacuo to yield compound XVf.

Example 36 N-allyl-3-methoxy- 14B-methyl-8-oxamorphinan XlVg). 

1. A COMPOUND HAVING THE FORMULA
 2. A compound of claim 1 having the formula
 3. A compound of claim 2 wherein R1 is -CH2-CH CH2, -CH2-C*CH,
 4. A compound of claim 2 wherein R1 is
 5. The compound of claim 2 wherein R1 is
 6. The compound of claim 2 wherein R1 is
 7. The compound of claim 2 wherein R1 is -CH2-CH CH2, R2 is H, and R3 is methyl; or the hydrochloride or tartrate salt thereof.
 8. The compound of claim 2 wherein R1 is H, R2 is H or methyl and R3 is H or methyl; or an acid addition salt thereof.
 9. The levorotatory isomer of the compound of claim
 2. 10. The dextrorotatory isomer of the compound of claim
 2. 11. The levorotatory isomer of the compound of claim
 4. 12. The dextrorotatory isomer of the compound of claim
 4. 13. The levorotatory isomer of the compound of claim
 5. 14. The levorotatory isomer of the compound of claim
 7. 15. The levorotatory isomer of the compound of claim
 3. 16. A compound having the formula
 17. A compound of claim 16 in which R1 is -CH2-CH, -CH2-CH CH2
 18. A compound of claim 17 wherein R1 is
 19. The compound of claim 17 wherein R1 is
 20. The compound of claim 17 wherein R1 is
 21. The compound of claim 17 wherein R1 is -CH2-CH CH2, R2 is H, and R3 is methyl; or the hydrochloride or tartrate salt thereof.
 22. The compound of claim 16 wherein R1 is H, R2 is H or methyl, and R3 is H or methyl; or an acid addition salt thereof.
 23. The levorotatory isomer of the compound of claim
 17. 24. The dextrorotatory isomer of the compound of claim
 17. 25. The levorotatory isomer of the compound of claim
 19. 26. The dextrorotatory isomer of the compound of claim
 19. 27. The levorotatory isomer of the compound of claim
 20. 28. The levorotatory isomer of the compound of claim
 21. 29. The levorotatory isomer of the compound of claim
 22. 30. The levorotatory isomer of the compound of claim
 23. 